DESCRIPTIONS (provided by applicant): Oxidative phosphorylation (OXPHOS) refers to the cell's core biochemical pathway for generating ATP. During the past 20 years, it's become abundantly evident that both inborn errors of metabolism as well as common, degenerative diseases stem from OXPHOS dysfunction. How defects in a single pathway transmit to other biochemical pathways to give rise to so many different syndromes and diseases is not clear. Moreover, diagnosing the inborn errors of mitochondrial metabolism is incredibly challenging. We hypothesize that a variety of biochemical pathways are conditionally activated in response to OXPHOS dysfunction, to permit the cell to adapt to the disease state. Using emerging "metabolomics" technologies, we propose to systematically identify such coupled biochemical pathways. We will utilize cells in culture as well as humans with known OXPHOS genetic diseases and profile cellular and plasma metabolites to determine how cellular metabolism adapts to defects in OXPHOS. The biochemical networks we uncover may shed insights into disease pathogenesis, may be targeted for therapy, and may immediately provide a biomarker for OXPHOS disease. The current study should lay the foundation for better understanding the role of OXPHOS in a number of common human diseases. PUBLIC HEALTH RELEVANCE: We have recently discovered a key cellular pathway that is altered in metabolic disorders such as diabetes. Using novel measurement technologies, we hope to better understand how alterations in these pathways give rise to disease in cells as well as in humans. If successful, our research could assist in the diagnosis of metabolic diseases, and also help motivate the design of novel therapies.